CN118791433A - Crystal form of oxalate of ilodoline intermediate and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of medicines and chemistry, and particularly relates to an oxalate crystal form of an illicit-lin intermediate and a preparation method thereof, wherein the crystal purity of the crystal form can reach more than 99%, compared with the solid form of the illicit-lin intermediate shown in the prior art formula II, the oxalate crystal form A and the oxalate crystal form B have the characteristics of high crystallinity, good stability, good filterability and high purity, and are used as intermediates for storage and provide a better scheme for subsequent production of products with higher purity, wherein the structures of the formulas II, the formulas A (formula II-1) and the formulas B (formula II-2) are shown as follows:

Description

Crystal form of oxalate of ilodoline intermediate and preparation method thereof

Technical Field

The invention relates to an oxalate crystal form of an illicit intermediate and a preparation method thereof, belonging to the technical field of medicines and chemistry.

Background

Illiqui (eluxadoline) is a mu-opioid receptor agonist and delta-opioid receptor antagonist developed by the company Johnson & Johnson, inc. in the United states, and was approved by the FDA for use in the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) in adults on day 27, 5, 2017. The chemical structure of the illiqui (formula I) is as follows:

2-methoxy-5- [ [ [ (1S) -1- (5-phenyl-1H-imidazol-2-yl) ethyl ] amino ] methyl ] benzoic acid methyl ester is a key high-grade intermediate (CAS number: 1391712-57-4) for synthesizing ilodoline, and the chemical structural formula is shown in (II):

WO2017191650 A1 discloses the preparation of the maleate Form M and the oxalate Form S of the Ilodozoline Intermediate (II), which has a good purification effect with respect to maleate, and a purity of 98.32%, but a low crystallinity.

WO2019197274A1 discloses the half oxalate form, but again the crystallinity is lower and the 2 theta angle has a significant inability to remove inorganic metal salt impurity peaks at about 39 °.

The preparation of oxalate is disclosed in IP.com Journal (2016), 16 (10A), 1-3, the crystallinity of oxalate obtained by repeated experiments is also poor, the material is pasty and adheres to the wall, the filtering property is poor, and the industrial scale-up production is not possible.

U.S. patent No. 10479769B2, example 1, discloses that methods a-D ultimately produce citrate, and that various solvent systems disclosed in the reference specification, for oxalate, fail to crystallize as an oil.

Generally, the low crystallinity or amorphous sample is unfavorable for the purification of the product, is easy to entrap solvents or impurities, and the amorphous sample has poor relative stability, so that better crystal forms and crystallization states are obtained, and the method has important significance for purification and subsequent storage.

Disclosure of Invention

The patent discloses an oxalate crystal form A and a half oxalate crystal form B of an Ilodoline Intermediate (II) and a preparation method thereof, wherein the salifying crystal purity can reach more than 99 percent, compared with the prior art report on the solid form of the Ilodoline Intermediate (II), the oxalate crystal form A and the oxalate crystal form B have the characteristics of high crystallinity, good stability, good filterability and high purity, and are used as intermediate storage and provide a better scheme for subsequent production of products with higher purity.

The invention provides an oxalate crystal form of an Illicit Intermediate (II), wherein the structure of the formula (II) is shown as follows:

the oxalate crystal form of the Ilodozoline Intermediate (II) is a crystal form A, wherein each molecule of the Ilodozoline Intermediate (II) contains oxalate with about 1 molecular number.

The invention discloses a compound crystal form A shown in a formula II-1, which is a salt formed by combining 1 molecule of 2-methoxy-5- [ [ [ (1S) -1- (5-phenyl-1H-imidazol-2-yl) ethyl ] amino ] methyl ] benzoate and 1 molecule of oxalic acid, and has the following structure:

According to the invention, the molar ratio of the oxalate in the oxalate crystal form A of the Ibrutin Intermediate (II) to the Ibrutin Intermediate (II) is 1:1, the ratio can be measured by adopting a conventional method such as a titration method, ion chromatography and the like, and the measured molar ratio of the oxalate to the Ibrutin Intermediate (II) is not necessarily exactly 1 molecule due to the influence of factors such as test errors, process fluctuation and the like, so that the 1 in the oxalate crystal form A of the Ibrutin Intermediate (II) can be understood as 1+/-0.1, and preferably 1+/-0.05.

The oxalate crystal form A of the Ilodozoline Intermediate (II) has characteristic peaks at 6.5+/-0.2 degrees, 10.6+/-0.2 degrees, 24.1+/-0.2 degrees, 24.6+/-0.2 degrees and 27.0+/-0.2 degrees in an X-ray powder diffraction spectrum detected by Cu-K alpha radiation.

Further, the oxalate crystal form A of the Ilodoline Intermediate (II) has characteristic peaks at 6.5+/-0.2 degrees, 10.6+/-0.2 degrees, 24.1+/-0.2 degrees, 24.6+/-0.2 degrees and 27.0+/-0.2 degrees and one or more of the following characteristic peaks in an X-ray powder diffraction pattern detected by using Cu-K alpha radiation ：12.4±0.2°,14.2±0.2°,15.9±0.2°,16.9±0.2°,17.2±0.2°,18.6±0.2°,19.1±0.2°,19.6±0.2°,20.4±0.2°,20.7±0.2°,21.3±0.2°,22.3±0.2°,23.0±0.2°,25.2±0.2°.

Further, the oxalate crystal form A of the Ilodoline Intermediate (II) has a characteristic peak at 6.5±0.2°,10.6±0.2°,12.4±0.2°,14.2±0.2°,15.9±0.2°,16.9±0.2°,17.2±0.2°,18.6±0.2°,19.1±0.2°,19.6±0.2°,20.4±0.2°,20.7±0.2°,21.3±0.2°,22.3±0.2°,23.0±0.2°,24.1±0.2°,24.6±0.2°,25.2±0.2°,27.0±0.2° and one or more of the following characteristic peaks in an X-ray powder diffraction pattern detected by Cu-K alpha radiation: 29.4 + -0.2 deg., 31.3 + -0.2 deg., 32.5 + -0.2 deg., 33.8 + -0.2 deg., 35.2 + -0.2 deg..

Further, the oxalate crystal form A of the Ilodozoline Intermediate (II) is shown in the specification and the figure 1 of the X-ray powder diffraction pattern.

In some embodiments of the present invention, the oxalate crystal form A of the Ilodoline Intermediate (II) has a DSC profile (heating rate: 10 ℃/min, heating from room temperature to 300 ℃ under nitrogen protection) with an endothermic peak at 172.6+ -5.0 ℃.

Further, the oxalate crystal form A of the Ilodoline Intermediate (II) has a DSC chart shown in figure 2 of the specification.

In some aspects of the invention, the thermogravimetric analysis (TGA) of the oxalate crystal form a of the Irudin Intermediate (II) begins to degrade at a scan rate of 10 ℃/min when heated from room temperature to 300 ℃ under nitrogen at 100.0±5.0 ℃ with a weight loss of about 1.0% and 180.3±5.0 ℃.

Further, the oxalate crystal form A, TGA of the intermediate (II) of the ilodoline is shown in figure 3 of the specification.

In some aspects of the invention, the oxalate crystal form a of the Ilodoline Intermediate (II) shows that crystals agglomerate into spheres under a Polarized Light Microscope (PLM), do not agglomerate, and are beneficial to filtration.

Further, the oxalate crystal form A and PLM of the Ilodoline Intermediate (II) are shown in figure 4 of the specification.

The purity of the oxalate crystal form A of the Ilodoline Intermediate (II) is more than or equal to 99.0 percent, preferably more than or equal to 99.2 percent, more preferably more than or equal to 99.5 percent, and most preferably more than or equal to 99.9 percent.

The invention provides a method for preparing oxalate crystal form A of an illicit-lin intermediate (II), which comprises the following steps:

(1) Dissolving the Ilodozoline Intermediate (II) in a mixed solvent of water and a ketone solvent at the temperature of between 10 and 50 ℃;

(2) And (3) dropwise adding an organic solution of oxalic acid into the solution obtained in the previous step, continuously stirring for 1-72 hours, preferably 1-36 hours, more preferably 1-5 hours, filtering for crystallization, and optionally drying to obtain the oxalate in the crystal form A.

Further, the ketone solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, preferably acetone;

Further, the volume ratio of the ketone solvent (such as acetone) to water is 0.05-20: 1, preferably 1 to 10:1, more preferably 6 to 9:1.

The weight-to-volume ratio (g/mL) of the Ilodoline Intermediate (II) to the solvent is 1 (1-20), preferably 1 (1-15), more preferably 1 (2-10), and most preferably 1 (5-6);

further, the molar amount of the Ilodoline Intermediate (II) to oxalic acid is 1:1 to 1.2, preferably 1:1.05 to 1.1;

Further, the organic solution in (2) is an ester solution, and the ester solution is ethyl formate, ethyl acetate, isopropyl acetate, etc., preferably ethyl acetate.

Further, the concentration of the organic solution of oxalic acid in (2) is preferably 10 to 20mg/mL, and the organic solution of oxalic acid is preferably dissolved at room temperature.

Further, the reaction temperature at which stirring is continued in (2) is 10 to 50 ℃, preferably 20 to 30 ℃.

Further, the drying is reduced pressure/air drying at 35-80 ℃, preferably 55-65 ℃.

The invention also provides an oxalate crystal form B of the Ilodoline Intermediate (II).

The oxalate crystal form B of the Iloprin Intermediate (II), wherein the Iloprin Intermediate (II) contains about 0.5 number of molecules of oxalate per molecule.

The invention discloses a compound crystal form B shown in a formula II-2, which is a salt formed by combining 1 molecule of 2-methoxy-5- [ [ [ (1S) -1- (5-phenyl-1H-imidazol-2-yl) ethyl ] amino ] methyl ] benzoic acid methyl ester and 0.5 molecule of oxalic acid:

According to the invention, the molar ratio of oxalate in the oxalate crystal form B of the Irudin Intermediate (II) to the Irudin Intermediate (II) is 0.5:1, the ratio can be measured by adopting a conventional method such as a titration method, ion chromatography and the like, and the measured molar ratio of oxalate to the Irudin Intermediate (II) is not necessarily exactly 0.5 due to the influence of factors such as test errors, process fluctuation and the like, so that the '0.5' in the oxalate crystal form B of the Irudin Intermediate (II) can be understood as '0.5+/-0.1', and preferably '0.5+/-0.05'.

The oxalate crystal form B of the Illiquiine Intermediate (II) has characteristic peaks at the positions of 4.0+/-0.2 degrees, 8.2+/-0.2 degrees, 10.9+/-0.2 degrees, 14.8+/-0.2 degrees, 18.0+/-0.2 degrees, 21.5+/-0.2 degrees and 21.9+/-0.2 degrees in an X-ray powder diffraction spectrum detected by Cu-K alpha radiation.

Further, the oxalate crystal form B of the Irudin Intermediate (II) has characteristic peaks at 4.0+/-0.2 degrees, 8.2+/-0.2 degrees, 10.9+/-0.2 degrees, 14.8+/-0.2 degrees, 18.0+/-0.2 degrees, 21.5+/-0.2 degrees, 21.9+/-0.2 degrees, 24.9+/-0.2 degrees, 25.2+/-0.2 degrees and one or more of the following characteristic peaks in an X-ray powder diffraction pattern detected by using Cu-K alpha radiation ：6.5±0.2°,7.1±0.2°,14.3±0.2°,16.1±0.2°,17.1±0.2°,19.0±0.2°,23.1±0.2°,23.5±0.2°,25.9±0.2°,26.8±0.2°,27.3±0.2°,28.0±0.2°,29.2±0.2°,30.1±0.2°,32.6±0.2°;

Further, the oxalate crystalline form B of the Irudin Intermediate (II) has a characteristic peak at about 4.0±0.2°,6.5±0.2°,7.1±0.2°,8.2±0.2°,10.9±0.2°,14.3±0.2°,14.8±0.2°,16.1±0.2°,17.1±0.2°,18.0±0.2°,19.0±0.2°,21.5±0.2°,21.9±0.2°,23.1±0.2°,23.5±0.2°,24.9±0.2°,25.2±0.2°,25.9±0.2°,26.8±0.2°,27.3±0.2°,28.0±0.2°,29.2±0.2°,30.1±0.2°,32.6±0.2° and one or more of the following characteristic peaks in the X-ray powder diffraction pattern detected using Cu-ka radiation: 9.8+ -0.2 °, 13.9+ -0.2 °, 19.7+ -0.2 °, 20.4+ -0.2 °, 20.7+ -0.2 °, 31.5+ -0.2 °.

Further, the oxalate crystal form B of the Ilodozoline Intermediate (II) is shown in the specification and the figure 5 of the X-ray powder diffraction pattern.

The DSC profile of the oxalate crystal form B of the Ilodoline Intermediate (II) (at a scanning speed of 10 ℃/min, under nitrogen protection, heating from room temperature to 300 ℃) at a scanning speed of 10 ℃/min, under nitrogen protection, heating from room temperature to 300 ℃ at 187.0+/-5.0 ℃) has an endothermic peak.

Further, the oxalate crystal form B of the Ilodoline Intermediate (II) has a DSC chart shown in figure 6 of the specification.

In some aspects of the invention, the thermogravimetric analysis (TGA) of the oxalate crystal form B of the Irudin Intermediate (II) begins to degrade at a scan rate of 10 ℃/min when heated from room temperature to 300 ℃ under nitrogen at 100.0±5.0 ℃ with a weight loss of about 0.35%,205.0±5 ℃.

Further, the oxalate crystal form B of the Ilodoline Intermediate (II) has a TGA spectrum shown in figure 7 of the specification.

In some embodiments of the invention, the oxalate crystal form B of the Ilodoline Intermediate (II) exhibits a rod-like crystal shape under a Polarized Light Microscope (PLM) and has a particle size of about 16 to 20 μm.

Further, the oxalate crystal form B and PLM of the Ilodoline Intermediate (II) are shown in figure 8 of the specification.

The purity of the oxalate crystal form B of the Ilodoline Intermediate (II) is more than or equal to 99.0 percent, preferably more than or equal to 99.2 percent, more preferably more than or equal to 99.5 percent, and most preferably more than or equal to 99.9 percent.

The invention also provides a method for preparing oxalate crystal form B of the Ilodoline Intermediate (II), which comprises the following steps:

(1) Dissolving the Ilodozoline Intermediate (II) in a mixed solvent of water and a ketone solvent at the temperature of between 30 and 60 ℃;

(2) And (3) dropwise adding an oxalic acid organic solution into the solution obtained in the previous step, continuously stirring for 1-72 hours, preferably 1-36 hours, more preferably 1-3 hours, filtering for crystallization, and optionally drying to obtain the oxalate in the crystal form B.

Further, the weight to volume ratio (g/ml) of the Ilodoline Intermediate (II) to the solvent is 1 (1-20), preferably 1 (1-15), more preferably 1 (2-10), most preferably 1: (5-6) g/ml.

Further, the volume ratio of the ketone solvent (such as acetone) to water in the (1) is 0.05-20: 1, preferably 1 to 10:1, more preferably 6 to 9:1, a step of;

further, the ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, preferably acetone.

Further, the molar amount of the Ilodoline Intermediate (II) to oxalic acid is 1:0.5 to 0.6, preferably 1:0.51 to 0.55;

Further, the organic solution in (2) is an ester solution, and the ester solution is ethyl formate, ethyl acetate, isopropyl acetate, etc., preferably ethyl acetate.

Further, the concentration of the oxalic acid organic solution in (2) is preferably 10 to 15mg/mL, and the oxalic acid organic solution is preferably dissolved at room temperature.

Further, the reaction temperature is 30 to 60 ℃, preferably 40 to 50 ℃ in the step (2) of continuously stirring.

Further, the drying is reduced pressure/air drying at 35-80 ℃, preferably 55-65 ℃.

The invention provides an application of oxalate crystal form A and crystal form B of an Ilodoline Intermediate (II) in preparing medicines for treating diarrhea-predominant irritable bowel syndrome (IBS-D) of adults.

The beneficial effects of the invention are as follows:

Because the material has strong hygroscopicity, is easy to be gelatinous, is difficult to purify, and is difficult to purify and remove impurities by the conventional method.

Compared with the solid form reported in the prior art, the oxalate of the Ilodozoline Intermediate (II) obtained by the invention has higher crystallinity and better impurity removing effect, the specific impurity removing effect is shown in table 1, the purity of the prepared product is more than 99.0%, and the product provides a raw material with higher quality for obtaining a high-purity finished product subsequently. The yield of the preparation process can reach more than 90%, and the yield is high, thereby being beneficial to reducing the production cost. The prepared material is spherical agglomerate or rod-shaped crystal, the product is well filtered, and compared with the prior art, the solid form is obtained, and the phenomenon of stickiness and difficult filtration is avoided. The product has good stability, is favorable for long-term storage and transportation, can store materials in advance for the production of subsequent finished products, and improves the subsequent production efficiency.

In conclusion, the oxalate crystal forms of the two types of the Ilodozoline Intermediates (II) and the preparation process thereof are provided, and compared with the prior art, the oxalate crystal forms have the advantages of high crystallinity, good impurity removal rate, stable product and high yield, and the purification and storage of the products are obviously improved.

TABLE 1 summary of impurity removal effects

Drawings

FIG. 1 is an X-ray powder diffraction (XPRD) diagram of the oxalate crystalline form A of the intermediate (II) of irudin.

Fig. 2 is a Differential Scanning Calorimetric (DSC) profile of oxalate crystal form a of the Ilodrin Intermediate (II).

Figure 3 is a thermogravimetric analysis (TGA) profile of oxalate crystal form a of the Ilodoline Intermediate (II).

Fig. 4 is a Polarized Light Microscope (PLM) photograph of oxalate crystal form a of the Ilodoline Intermediate (II).

Fig. 5 is an X-ray powder diffraction (XPRD) pattern of oxalate crystal form B of the intermediate (II) of ibridronate.

Fig. 6 is a Differential Scanning Calorimetric (DSC) profile of oxalate form B of the Ilodrin Intermediate (II).

Figure 7 is a thermogravimetric analysis (TGA) profile of oxalate crystal form B of the Ilodoline Intermediate (II).

Fig. 8 is a polarizing microscope (PLM) view of oxalate crystal form B of the Ilodoline Intermediate (II).

FIG. 9 is an amorphous X-ray powder diffraction (XPRD) chart of the oxalate salt of the intermediate (II) of ilodoline in comparative example 2 of the present invention.

FIG. 10 is a diagram of the superposition of IP.com Journal (2016), 16 (10A), 1-3 and forms A and B of the present invention.

Detailed Description

Comparative example 1

Salt screening of Irudin Intermediate (II)

Because the Ilodozoline Intermediate (II) is oily, the method is unfavorable for impurity removal, storage and transportation. The physical properties are improved by salifying the different acids.

About 30mg of the Ilodozoline Intermediate (II) was weighed, and hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and acetic acid were selected as acid ligands for salt formation attempts, which showed that no good solid form could be obtained, as shown in table 2.

TABLE 2 salt screening

* Reference is made to the preparation method of example 4 of the present invention;

Table 2 the results show that: through a series of ligand acid salification screening experiments, the Irudin Intermediate (II) is difficult to crystallize with the ligand acid to form crystal salt, so that amorphous, clear liquid is generated without solid precipitation or oily substance is generated in production, and the risks of difficult filtration, extremely low yield or almost no solid precipitation and the like of impurities are encountered.

Comparative example 2

Oxalate crystal form screening of Iloduoline Intermediate (II)

Salt formation studies on the Ilodozoline Intermediate (II) with oxalic acid and screening of the amorphous form of the Ilodozoline Intermediate (II) oxalate revealed that only in most conventional solvents was obtained as an oil or amorphous.

The results of screening the oxalate forms are shown in tables 3 and 4.

TABLE 3 salt formation screening of oxalic acid

TABLE 4 oxalate Crystal form screening

Comparative example 3

Amorphous preparation crystallization process

1.0G (2.7 mmol, initial purity 96.8%) of oily Ilodoline Intermediate (II) is weighed, 5mL of acetone is added for dissolving, 1.05eq of oxalic acid ethyl acetate solution (256 mg of oxalic acid and 15mL of ethyl acetate are dissolved) is slowly added, a large amount of caking white solid is precipitated, the caking solid is uniformly dispersed after beating for 1-3h, the filtration is carried out under reduced pressure, a sample has a viscosity-changing phenomenon in the filtration process, the solid is dried by blowing at 60 ℃, the solid is caking, and the XRPD is shown in figure 9. 1.05g of a dry sample was obtained, with a yield of 84% and a purity of 98.84%.

Wherein the starting materials and final product impurity spectra are shown in Table 1.

EXAMPLE 1 acquisition of the oxalate Crystal form A/B X-ray powder diffraction (XPRD) Spectrometry of the Irudor Intermediate (II)

XPRD spectrum of oxalate crystal form A/B of the Ilodozoline Intermediate (II) is acquired on a Bruker D8 ADVANCE diffractometer, and the method parameters of X-ray powder diffraction are as follows:

X-ray reflection parameters: cu, K alpha

Tube voltage: 40 kilovolts (kV)

Tube current: 40 milliamperes (mA)

Slit: 2# scattering slit: 1 °,3# anti-scatter slit: 1 °,4# receiving slit: 0.3mm.

Scanning mode: stepping

Step angle: 0.02 °, sampling time: 0.2s;

Scanning range: from 3.0 to 40.0 DEG

The diffraction results of the oxalate crystal form A of the Irudin Intermediate (II) are shown in fig. 1 and table 5, and the X-ray powder diffraction pattern of the oxalate crystal form A of the Irudin Intermediate (II) has corresponding characteristic diffraction peaks at corresponding positions of 2 theta values.

TABLE 52 theta values of the XRPD absorption peaks for oxalate Crystal form A of Irudorine Intermediate (II)

The diffraction results of the oxalate crystal form B of the Irudin Intermediate (II) are shown in fig. 5 and table 6, and the XRPD pattern of the oxalate crystal form B of the Irudin Intermediate (II) has corresponding characteristic diffraction peaks at the corresponding positions of the 2θ values.

TABLE 62 theta values of the XRPD absorption peaks for oxalate Crystal form B of Irudorine Intermediate (II)

EXAMPLE 2 DSC collection of oxalate Crystal form A/B of Irudorin Intermediate (II)

The DSC spectrum is acquired on TA Instruments Discovery DSC instrument, and the method parameters of the differential scanning calorimeter analysis are as follows:

Scanning rate: 10 ℃/min

Protective gas: nitrogen gas

DSC data acquisition method of oxalate crystal form A/B of the Ilodozoline Intermediate (II) is as follows:

3-5mg of the sample is weighed and placed in an aluminum crucible, and after sealing by using a non-sealing cover, the sample is loaded on a DSC instrument for collection. The sample was heated from room temperature to 300 ℃ under nitrogen at a scan rate of 10 ℃/min.

DSC data of oxalate crystalline form A of the Ilodoline Intermediate (II) are shown in FIG. 2, and an endothermic peak appears at 172.6.+ -. 5.0 ℃.

DSC data of oxalate form B of the Ilodoline Intermediate (II) are shown in FIG. 6, and endothermic peaks appear at 187.0.+ -. 5.0 ℃.

EXAMPLE 3 TGA Spectrometry acquisition of the oxalate Crystal form A/B of the Irudorine Intermediate (II)

The TGA spectrum is acquired on TA Instruments Discovery TGA instruments, and the method parameters of the thermogravimetric analysis are as follows:

Scanning rate: 10 ℃/min

Protective gas: nitrogen gas

5-10Mg of the sample was weighed and placed in a platinum pan and collected on a sample-loaded TGA instrument. The sample was heated from room temperature to 300 ℃ under nitrogen at a scan rate of 10 ℃/min.

TGA data for oxalate crystalline form a of the Ilopri Intermediate (II) is shown in figure 3, losing about 1.0% weight at 100.0±5.0 ℃.

TGA data for oxalate form B of the Ilopri Intermediate (II) is shown in fig. 7, with a weight loss of about 0.35% at 100.0±5.0 ℃.

EXAMPLE 4 preparation of the oxalate Crystal form A of the Isadozoline Intermediate (II)

1.0G (2.7 mmol, purity 96.80%) of oily Irinotecan Intermediate (II) is weighed, 5mL of acetone/water 9/1 mixed solvent is added for dissolving, 1.05eq of oxalic acid ethyl acetate solution (256 mg of oxalic acid is dissolved in 15mL of ethyl acetate) is slowly added for crystal growth at room temperature, after stirring for 1-3h, decompression filtration and air drying at 60 ℃ are carried out, and 1.12g of the oxalate crystal form A of the Irinotecan Intermediate (II) is obtained, the yield is 90%, and the purity is 99.17%. The XRPD pattern of this product is shown in figure 1. The results of comparison with the impurity profile of the starting material are shown in Table 1.

EXAMPLE 5 preparation of the oxalate Crystal form B of the Irudorine Intermediate (II)

1.2G (3.3 mmol, purity 96.80%) of oily Irinotecan Intermediate (II) is weighed, 5mL of acetone/water 9/1 mixed solvent is added for dissolving, then 0.6eq of ethyl oxalate solution (178 mg of oxalic acid is slowly added dropwise, and dissolved in 12mL of ethyl acetate) is slowly added, a large amount of white solid is separated out, then the temperature is raised to 50 ℃ for stirring, the temperature is kept for crystal growth for 1-3h, then 1 ℃/min is cooled to 5 ℃, the temperature is reduced, the filtration is carried out under reduced pressure, the air blast drying is carried out at 60 ℃, and 1.27g of oxalate crystal form B of the Irinotecan Intermediate (II) is obtained, the yield is 94%, and the purity is 99.94%. The XRPD pattern of this product is shown in figure 5. The results of comparison with the impurity profile of the starting material are shown in Table 1.

EXAMPLE 6 evaluation of stability of oxalate Crystal form A and Crystal form B of Irudorin Intermediate (II)

The oxalate crystal form A and the crystal form B of the intermediate (II) of the irinotecan are weighed about 20mg, and are respectively placed at room temperature/75% Relative Humidity (RH) in an open mode, and are respectively sampled at 1/2/4 week at room temperature/92% RH,25 ℃/60% RH and 40 ℃/75% RH, the purity and the crystal form change are detected, and the result shows that the purity of the oxalate crystal form A and the crystal form B of the intermediate (II) of the irinotecan have no obvious change, which indicates that the physicochemical properties of 2 solid forms are stable, and the long-term storage and transportation of materials are facilitated.

The stability results of the oxalate crystalline form a of the Ilopri Intermediate (II) are summarized in table 7.

The stability results of oxalate form B of the Ilopri Intermediate (II) are summarized in table 8.

TABLE 7 oxalate crystalline form A of Ilodoline Intermediate (II)

TABLE 8 oxalate crystalline form B of Ilodoline Intermediate (II)

In conclusion, the oxalate crystal form A and the oxalate crystal form B of the obtained Iloprin Intermediate (II) have unique XRPD patterns, high crystallinity, simple process for preparing the two crystal forms, high yield, obvious purification and impurity removal effects, good product stability, contribution to amplified production, and higher quality and stability of raw materials for preparing the iloprin in the later stage.

Claims (10)

1. An oxalate crystalline form of an irudin intermediate II, wherein the structure of formula II is as follows:

II

The oxalate crystal form of the ilodoline intermediate II is a salt crystal form A formed by combining a compound of a molecular formula II with 1 molecule of oxalic acid, wherein the structure is shown in the following formula II-1:

II-1

The 2 theta in the X-ray powder diffraction pattern detected by using Cu-K alpha radiation of the crystal form A has characteristic peaks at 6.5+/-0.2 degrees, 10.6+/-0.2 degrees, 24.1+/-0.2 degrees, 24.6+/-0.2 degrees and 27.0+/-0.2 degrees;

Or the oxalate crystal form of the ilodoline intermediate II is a salt crystal form B formed by combining a compound with a molecular formula II of 1 and 0.5 molecule of oxalic acid, wherein the structure is shown in the following II-2:

II-2

In the X-ray powder diffraction pattern of the crystal form B detected by Cu-K alpha radiation, the 2 theta has characteristic peaks at the positions of 4.0+/-0.2 degrees, 8.2+/-0.2 degrees, 10.9+/-0.2 degrees, 14.8+/-0.2 degrees, 18.0+/-0.2 degrees, 21.5+/-0.2 degrees and 21.9+/-0.2 degrees.

2. Form a according to claim 1, wherein the form a has a characteristic peak at 6.5±0.2°,10.6±0.2°,24.1±0.2°,24.6±0.2°,27.0±0.2° and one or more of the following characteristic peaks in an X-ray powder diffraction pattern using Cu-ka radiation detection ：12.4 ±0.2°,14.2 ±0.2°,15.9 ±0.2°,16.9 ±0.2°,17.2 ±0.2°,18.6 ±0.2°,19.1 ±0.2°,19.6 ±0.2°,20.4 ±0.2°,20.7 ±0.2°,21.3 ±0.2°,22.3 ±0.2°,23.0 ±0.2°,25.2 ±0.2°;

Or preferably form a, the 2 theta in the X-ray powder diffraction pattern detected using Cu-ka radiation has a characteristic peak at 6.5 ±0.2°,10.6 ±0.2°,12.4 ±0.2°,14.2 ±0.2°,15.9 ±0.2°,16.9 ±0.2°,17.2 ±0.2°,18.6 ±0.2°,19.1 ±0.2°,19.6 ±0.2°,20.4 ±0.2°,20.7 ±0.2°,21.3 ±0.2°,22.3 ±0.2°,23.0 ±0.2°,24.1 ±0.2°,24.6 ±0.2°,25.2 ±0.2°,27.0±0.2° and one or more of the following characteristic peaks: 29.4 0.2 deg., 31.3 deg. + -0.2 deg., 32.5 deg. + -0.2 deg., 33.8+ -0.2 DEG, 35.2+ -0.2 DEG;

Or preferably form a has an X-ray powder diffraction pattern using Cu-ka radiation substantially as shown in figure 1;

Or preferably the DSC profile of form a has an endothermic peak at 172.6±5.0 ℃; preferably, the form a has a DSC profile as shown in figure 2;

Or preferably the TGA profile of form a loses weight about 1.0% at 100.0±5.0 ℃, and begins to degrade at 180.3±5.0 ℃; preferably, the form a has a TGA profile shown in fig. 3;

Or preferably the form a has a PLM profile as shown in figure 4.

3. A process for the preparation of form a according to claim 1 or 2, comprising the steps of:

(1) Dissolving the ilodozoline intermediate II in a mixed solvent of water and a ketone solvent at the temperature of 10-50 ℃;

(2) And (3) dropwise adding an organic solution of oxalic acid into the solution obtained in the previous step, continuously stirring for 1-72 hours, preferably 1-36 hours, more preferably 1-5 hours, filtering for crystallization, and optionally drying to obtain the oxalate in the crystal form A.

4. The method of claim 3, wherein the volume ratio of ketone solvent to water is 0.05-20: 1, preferably 1 to 10:1, more preferably 6 to 9:1, a step of;

Preferably, the ketone solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, further preferably acetone;

preferably, the weight to volume ratio g/mL of the ilodoline intermediate II to the solvent is 1 (1-20), preferably 1 (1-15), more preferably 1 (2-10), most preferably 1 (5-6);

Preferably, the molar amount of the Ilodoline Intermediate (II) to oxalic acid is 1:1 to 1.2, preferably 1:1.05 to 1.1;

preferably, the organic solution in the step (2) is an ester solution, and the ester solution is ethyl formate, ethyl acetate, isopropyl acetate, and the like, preferably ethyl acetate;

Preferably, the concentration of the organic solution of oxalic acid in the step (2) is 10-20 mg/mL, and the organic solution of oxalic acid is preferably dissolved at room temperature;

preferably, the reaction temperature of continuous stirring in the step (2) is 10-50 ℃, preferably 20-30 ℃;

preferably, the drying in step (2) is reduced pressure/air drying at 35-80 ℃, preferably 55-65 ℃.

5. Form B according to claim 1, characterized in that the form B has characteristic peaks at 4.0±0.2°,8.2±0.2°,10.9±0.2°,14.8±0.2°,18.0±0.2°,21.5±0.2°,21.9±0.2°,24.9±0.2°,25.2±0.2° and has one or more of the following characteristic peaks in an X-ray powder diffraction pattern using Cu-ka radiation detection ：6.5±0.2°,7.1±0.2°,14.3±0.2°,16.1±0.2°,17.1±0.2°,19.0±0.2°,23.1±0.2°,23.5±0.2°,25.9±0.2°,26.8±0.2°,27.3±0.2°,28.0±0.2°,29.2±0.2°,30.1±0.2°,32.6±0.2°.

6. Form B according to claim 5, characterized in that the form B has a characteristic peak at about 4.0±0.2°,6.5±0.2°,7.1±0.2°,8.2±0.2°,10.9±0.2°,14.3±0.2°,14.8±0.2°,16.1±0.2°,17.1±0.2°,18.0±0.2°,19.0±0.2°,21.5±0.2°,21.9±0.2°,23.1±0.2°,23.5±0.2°,24.9±0.2°,25.2±0.2°,25.9±0.2°,26.8±0.2°,27.3±0.2°,28.0±0.2°,29.2±0.2°,30.1±0.2°,32.6 ±0.2° in the X-ray powder diffraction pattern detected using Cu-ka radiation and has one or more of the following characteristic peaks: 9.8+ -0.2 °, 13.9+ -0.2 °, 19.7+ -0.2 °, 20.4+ -0.2 °, 20.7+ -0.2 °, 31.5+ -0.2 °;

or preferably form B, an X-ray powder diffraction pattern using Cu-ka radiation is substantially as shown in figure 5.

7. Form B according to claim 1 or 5 or 6, characterized in that the DSC profile of form B has an endothermic peak at 187.0±5.0 ℃; preferably, the form B has a DSC profile as shown in figure 6;

Or preferably the TGA profile of form B loses weight about 0.35% at 100.0±5.0 ℃, and begins to degrade at 205.0±5 ℃; preferably, the form B has a TGA profile shown in fig. 7;

or preferably, the crystal form B is displayed under PLM, the crystal is in a rod shape, and the particle size is 16-20 mu m; preferably, the form B has a PLM profile as shown in fig. 8;

or preferably the purity of the oxalate crystals form B of the Irudin Intermediate (II) is not less than 99.0%, preferably not less than 99.2%, more preferably not less than 99.5%, most preferably not less than 99.9%.

8. A process for the preparation of form B according to claim 1 or 5 or 6, comprising the steps of:

(1) Dissolving the Ilodozoline Intermediate (II) in a mixed solvent of water and a ketone solvent at the temperature of 30-60 ℃;

(2) Dropwise adding an oxalic acid organic solution into the solution obtained in the previous step, continuously stirring for 1-72 hours, preferably 1-36 hours, more preferably 1-3 hours, filtering and crystallizing, and optionally drying to obtain the oxalate crystal form B; wherein the structure of formula II is as follows:

。

9. the process according to claim 8, wherein the weight to volume ratio g/ml of the ilodoline intermediate II to the solvent is 1 (1-20), preferably 1 (1-15), more preferably 1 (2-10), most preferably 1: (5-6) g/ml;

preferably, in the step (1), the volume ratio of the acetone to the water is 0.05-20: 1, preferably 1 to 10:1, more preferably 6 to 9:1, a step of;

Preferably, the ketone solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, preferably acetone;

preferably, the molar amount of the Ilodoline Intermediate (II) to oxalic acid is 1:0.5 to 0.6, preferably 1:0.51 to 0.55;

preferably, the organic solution in the step (2) is an ester solution, and the ester solution is ethyl formate, ethyl acetate, isopropyl acetate, and the like, preferably ethyl acetate;

preferably, in the step (2), the concentration of the oxalic acid organic solution is 10-15 mg/mL, and the oxalic acid organic solution is preferably dissolved at room temperature;

preferably, the reaction temperature is 30-60 ℃, preferably 40-50 ℃ in the step (2) of continuously stirring;

Preferably, the drying in said step is reduced pressure/air drying at 35-80 ℃, preferably 55-65 ℃.

10. The use of form a according to any one of claims 1-2 or form B according to any one of claims 1, 5, 6 for the manufacture of a medicament for the treatment of IBS-D, diarrhea-predominant irritable bowel syndrome in adults.